Adamantane as a Brain-Directed Drug Carrier for Poorly Absorbed Drug. 2. AZT Derivatives Conjugated with the 1-Adamantane Moiety

Five AZT (azidothymidine) prodrugs conjugated with the 1-adamantane moiety via an ester bond were synthesized to improve the transport of AZT into the central nervous system (CNS). Inin vitro degradation studies with rat and human plasma, it was demonstrated that the prodrugs were degradated enzymat...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 1994-04, Vol.83 (4), p.481-484
Main Authors: Tsuzuki, Noriko, Hama, Teruo, Kawada, Mitsuhiro, Hasui, Akihiro, Konishi, Ryoji, Shiwa, Satoshi, Ochi, Yoshihito, Futaki, Shiroh, Kitagawa, Kouki
Format: Article
Language:English
Subjects:
Adamantane - pharmacokinetics
Adamantane - pharmacology
AIDS/HIV
Animals
Blood-Brain Barrier - physiology
Brain - metabolism
Chemical Phenomena
Chemistry, Physical
Chromatography, High Pressure Liquid
Drug Carriers
Humans
Hydrolysis
In Vitro Techniques
Male
Prodrugs - chemical synthesis
Prodrugs - pharmacokinetics
Prodrugs - pharmacology
Rats
Rats, Wistar
Zidovudine - administration & dosage
Zidovudine - analogs & derivatives
Zidovudine - pharmacokinetics
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Summary:Five AZT (azidothymidine) prodrugs conjugated with the 1-adamantane moiety via an ester bond were synthesized to improve the transport of AZT into the central nervous system (CNS). Inin vitro degradation studies with rat and human plasma, it was demonstrated that the prodrugs were degradated enzymatically and converted quantitatively to their parent drug, AZT. As assessed by octanol–buffer partitioning, the prodrugs were much more lipophilic than AZT and were expected to penetrate the blood–brain barrier (BBB) readily. Inin vivostudies, in which the prodrugs were administered intravenously to rat, the prodrugs in brain tissue were detected at 7–18 times higher concentrations than AZT in spite of the negligible amount of the prodrug in the cerebrospinal fluid. These results indicate that the introduction to AZT of the 1-adamantane moiety results in the enhancement of the BBB penetration. This pharmaceutical approach would be beneficial for the efficient treatment of the CNS infection by human immunodeficiency virus.
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.2600830407